Phosphorylation as a method of tuning the enantiodiscrimination potency of quinine-An NMR study

Article abstract of DOI:10.1002/chir.22000

Quinines phosphorylated at the C-9 hydroxyl group (diphenyl and diethyl phosphates) were synthesized and validated as novel effective chiral solvating agents in two alternative methods based on ¹H and ³¹P NMR spectroscopy. Tested wit

Full text of DOI:10.1002/chir.22000

CHIRALITY 24:318–328 (2012)
Phosphorylation as a Method of Tuning the Enantiodiscrimination
Potency of Quinine—An NMR Study
1
1
1
1
2
´
´
ŁUKASZ GORECKI, ŁUKASZ BERLICKI, ARTUR MUCHA, PAWEŁ KAFARSKI, KATARZYNA SLEPOKURA, AND
1
´
*
EWA RUDZINSKA-SZOSTAK
1Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wrocław, Poland
2Faculty of Chemistry, University of Wrocław, Wrocław, Poland
ABSTRACT
Quinines phosphorylated at the C-9 hydroxyl group (diphenyl and diethyl phos-
phates) were synthesized and validated as novel effective chiral solvating agents in two alterna-
1
tive methods based on H and 31P NMR spectroscopy. Tested with a representative set of race-
1
mic analytes, the title compounds induced shift nonequivalence effects in H NMR signals with
values up to 0.1–0.2 ppm for 3,5-dinitrobenzoyl-substituted amino acids. In terms of enantiodif-
ferentiation extent and application range, introduction of a phosphate group was proven to be
superior compared to the action of nonmodified quinine. Interestingly, a temperature decrease
to reach the slow exchange conditions also produced nonequivalences in the 31P NMR spectra
of the selectors. Comprehensive NMR analysis showed the existence of two conformations
(closed 1 and 2) for both quinines in their free forms and the open 3 arrangement for the proto-
nated ones. The crystal structure of diethylphosphorylquinine hydrochloride dichloromethane
hemisolvate revealed a similar conformation to that observed in solution. Structures of com-
plexes of phosphorylated quinines with selected ligands were determined with the use of NMR-
C
VV
based molecular modeling studies. Chirality 24:318–328, 2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: alkaloids; phosphorylation; conformation analysis; chiral auxiliaries; NMR
spectroscopy
INTRODUCTION
binaphthyl compounds, alkylarylcarbinols and others in the
original works of Salvadori et al.14,15 Being inexpensive and
soluble in standard NMR solvents, nonderivatized quinine
has been applied for the characterization of composition of
compounds and the enantioselectivity of selected reactions,
Quinine, the major component of Cinchona alkaloids, rep-
resents one of the most privileged molecules exploited in
chiral recognition applications.1 Its structural arrangement
involves the simultaneous presence of a methoxy-substi-
tuted quinoline system and constrained bicyclic vinyl-substi-
tuted quinuclidine tertiary amine system, all connected by a
hydroxymethylene linker. The unique three-dimensional as-
sembly of quinine is emphasized by the presence of four
carbon and one nitrogen stereogenic centers. These fea-
tures together with multifunctional heteroatom variety offer
different kinds of potentially stereoselective contacts,
including ion pairing, hydrogen bonding, dipole–dipole, p-p
and van der Waals interactions. The chiral recognition dem-
onstrated by quinine, influenced by additional conforma-
tional factors, has been the matter of numerous theoretical
and spectroscopic investigations (for representative recent
examples, see Refs. 2–7). As a consequence, quinine- and
quinine-based chiral auxiliaries and catalyst components
have been successfully employed in asymmetric synthe-
sis.1,8 Stereoselective techniques of analysis and the separa-
tion of enantiomers represent additional subjects of great in-
terest in this field. Appropriate derivatives have served as
chiral stationary phases in HPLC or CEC9–12 or background
electrolyte additives in nonaqueous CE.13 Finally, they have
been found to be chiral solvating agents (CSAs) in the
NMR determination of the enantiomeric composition of vari-
ous analytes.
1
mainly those involving hydroxyl derivatives. Thus, H NMR
has served to determine the optical purity of secondary alco-
hols obtained through the enantioselective addition of dieth-
ylzinc to furaldehydes,16 as well as for the analysis of b-
hydroxy esters17 and cyclic hemiacetals and methyl acetals.18
Secondary and tertiary a-aryl-a-trifluoromethyl alcohols and
hydroxyesters were studied by the use 19F NMR,19 whereas
31P NMR allowed enantiodiscrimination of 1-hydroxy,20 1,2-
dihydroxyalkanephosphonates21 and N-benzyloxycarbonyla-
mino-phosphonates22 in our group. Triphenyltin-modified
alcohols and acids showed chemical shift anisochrony in
119Sn NMR.23 The encouraging results of these applications
induced further attempts to modify the fundamental quinine
structure, preferentially at the C9 and C11 positions. Consist-
ent with their successful chromatographic utility, C9-carba-
moylated derivatives were tested as CSAs against a range
This article is dedicated to Prof. Francisco Palacios on the occasion of his
60th anniversary.
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: The work was financed by a statutory activity sub-
sidy from the Polish Ministry of Science and Higher Education for the Fac-
ulty of Chemistry of Wrocław University of Technology.
´
*Correspondence to: Ewa Rudzinska-Szostak, Department of Bioorganic
Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wyb-
´
rzez˙e Wyspianskiego 27, Wrocław 50-370, Poland.
The formation of dynamic diastereomeric solvates with
quinine produces diagnostic nonequivalences in different
enantiotopic nuclei. Accordingly, selected proton and fluo-
rine resonances were indicative of enantiomers of substituted
E-mail: ewa.rudzinska@pwr.wroc.pl
Received for publication 28 September 2011; Accepted 14 December 2011
DOI: 10.1002/chir.22000
Published online 17 February 2012 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2012 Wiley Periodicals, Inc.

TUNING THE ENANTIODISCRIMINATION POTENCY OF QUININE
319
The figure was made using an XP program.38 Crystal data for
2b3HCl30.5CH2Cl2: C24.5H35Cl2N2O5P, M 5 539.41, orthorhombic,
chiral substrates, including amines, acids, amides and N-pro-
tected amino acids.24–27 Additionally, penta- and hexavalent
organophosphorus species have been found to be important
structural elements of synthetic receptors.28,29 In particular,
˚
space group P21212, a 5 11.868(4), b 5 28.248(9), c 5 7.999(3) A, V 5
2681.6(16) A , Z 5 4, T 5 100(2) K, l 5 0.34 mm21, analytical absorp-
3
˚
tion correction (Tmin 5 0.957, Tmax 5 0.978), 20,122 measured reflec-
thiophosphonates,30,31
1,1’-dinaphthyl-2,2’diylphosphoric
tions, 7428 independent refl., 3529 reflections with I > 2r(I), hmin
5
acid32,33 and dianaphthyl- and/or o-cresol-derived hexacoor-
dinated phosphates34,35 are effective CSAs in NMR spectros-
copy. Importantly, the synthetic availability of such com-
pounds should not be a limiting aspect of their applications.
In this work, a combination of an easily available, unique
chiral scaffold of quinine with a phosphate moiety that shows
good complexing properties toward different ligands was
investigated. We explore a novel, synthetically feasible way of
derivatizing the C9 hydroxyl and evaluate its influence on the
enantiodiscrimination effect. The functionalization led to phos-
phorylated quinines that could offer new potential interactions
with analytes via oxygen atom-rich moieties. The modified
2.768, hmax 5 30.078, R1 5 0.048, wR2 (all data) 5 0.052, Dq (max/min)
5 0.39/20.46 eA23. CCDC-831387 contains the supplementary crystallo-
˚
graphic data for this article. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Molecular Modeling
All calculations were performed with the use of Discovery Studio v 2.5
(Accelrys). Optimizations were conducted with application of the
CHARMm forcefield, the Momany-Rone method of atom partial charge
computation, the Smart Minimizer algorithm, and up to an RMS gradient
˚
0.01 A. Minimizations were performed in two steps: (a) with the con-
strains obtained from NMR measurements and (b) without any con-
straints.
1
compounds were subsequently validated as CSAs in H NMR
spectroscopy under fast exchange conditions against a collec-
tion of model chiral selectands. Using the characteristic fea-
tures of the selector, the recognition phenomenon was addi-
tionally studied by means of 31P NMR at low temperature to
reach slow exchange conditions. Detailed conformational anal-
ysis of phosphorylated quinine in the free form, protonated
and complexed with a selected ligands was performed with
the use of the NMR and molecular modeling techniques.
Chemistry
Ligands 3g-n are commercially available (Aldrich). Racemic com-
pounds 3a-f were synthesized according to the standard methods.39
Enantiomerically pure 3a and 3b were obtained using the method pub-
lished by Pirkle.40 The monochloride of nonmodified quinine and the
phosphorylated quinines were prepared by the addition of an equivalent
amount of methanolic hydrogen chloride to the free amine followed by
solvent evaporation.
MATERIALS AND METHODS
General
General Procedure of Phosphorylation
t-BuOK (10.2 mmol, 1.145 g) was added in one portion to a solution of
quinine (10 mmol, 3.244 g) in dry tetrahydrofuran (100 ml) and then
cooled to –788C. After 0.5 h, diethyl chlorophosphate (10.5 mmol, 1.812
g) or diphenyl chlorophosphate (10.5 mmol, 2.821 g) dissolved in 3 ml of
THF was added dropwise to the reaction mixture. Stirring was continued
for 2 h at –788C and overnight at room temperature. The volatile compo-
nents were evaporated under reduced pressure, and the residue was dis-
solved in ethyl acetate, washed with water and dried over MgSO4. The
solvent was removed on a rotary evaporator, and the final product was
purified via column chromatography using silica gel and an ethyl ace-
tate/methanol mixture (4:1) as the eluent. The solvents were removed
from the collected fractions, and the residue was treated with diethyl
ether and stored in the fridge for crystallization. The resulting phospho-
rylated quinine was filtered after a few days.
All solvents and reagents purchased from commercial suppliers
(Aldrich, Sigma, Merck, POCh, Armar) were of analytical grade and
were used without further purification. High resolution mass spectra
were measured on an LCT Premier XE (Waters) apparatus with electro-
spray ionization (positive ion mode). NMR experiments were performed
on a Bruker AvanceTM 600 MHz.
NMR Measurements
Measurements at 298, 293, 283, and 250 K were made in CDCl3 solu-
tion. To improve the solubility of ligands 3a,i,f, 3b, and 3c, 2, 4, and 6%
DMSO were added to the CDCl3 solutions, respectively. Measurements
at 180 and 200 K were performed in CD2Cl2. The signal assignment of
the 1H spectra of receptors 1 and 2b, their hydrochloride salts and their
1:1 complexes with S-3b at 50 mM in CDCl3 at 298 K and 10 mM in
CD2Cl2 at 200 K was assisted by 1H-1H COSY, ROESY and 1H-13C HSQC
spectra. Typical 1D and 2D ROESY spectra were recorded in phase-sen-
sitive mode by employing a spin lock of 0.1 s at 200 K and 01–1.2 s at
298 K. Coupling constants were determined from 1H inverse gated
decoupled 31P spectra.
9-O-Diphenylphosphorylquinine (2a)
Colorless crystals, yield 66%, m.p. 97.5–98.58C. HRMS (TOF MS ESI):
m/z calcd for C32H34N2O5P1: 557.2205 [M1H]1; found: 557.2193. 1H
3
NMR (600 MHz, CDCl3, 258C): d (ppm) 8.68 (d, JH,H 5 4.5 Hz, 1H; H-
2), 8.01 (d, 3JH,H 5 9.4 Hz, 1H; H-8), 7.35 (m, 5H; H-7, H-5, H-3, 2H o-Ph)
7.20 (m, 3H; 1H p-Ph, 2H m-Ph), 7.02 (m, 2H; o-Ph’), 6.98 (m, 1H; p-Ph’),
6.71 (d, 2H; m-Ph’), 6.24 (br, 1H; H-11), 5.85 (m, 1H; H-20), 5.02 (m, 2H;
H-21), 3.90 (s, 3H; OCH3), 3.40 (br, 1H; H-12), 3.08 (br, 1H; H-18’), 2.99
(br, 1H; H-14’), 2.60 (m, 2H; H-18, H-14), 2.27 (br, 1H; H-15), 1.90 (br,
1H; H-17), 1.86 (br, 1H; H-16), 1.70 (br, 1H; H-19’), 1.65 (br, 1H; H-17’),
1.52 (br, 1H; H-19). 13C NMR (151 MHz, CDCl3, 258C): d (ppm) 158.0
Crystal Structure
The crystallographic measurement for 2b hydrochloride dichlorome-
thane hemisolvate (2b3HCl30.5CH2Cl2; colorless; 0.35 3 0.10 3 0.07
mm3) was performed on a Xcalibur PX automated four-circle diffractome-
ter with the graphite-monochromatized Mo-Ka radiation at 100(2) K.
Data collection, cell refinement, and data reduction and analysis were
carried out with CrysAlisCCD and CrysAlisRED, respectively.36 Analyti-
cal absorption correction was applied to the data with the use of CrysA-
lisRED. The structure was solved by direct methods using SHELXS-97,37
2
2
(C-16), 150.5 (d, JC,P 5 7.0 Hz; C-28), 149.9 (d, JC,P 5 6.6 Hz; C-35),
147.3 (C-11), 144.9 (C-13), 142.4 (C-19), 141.8 (C-22), 131.8 (C-18), 129.8
(2C; C-29, C-33), 129.3 (2C; C-36, C-40), 126.8 (C-14), 125.5 (C-31), 125.2
(C-38), 121.9 (C-17), 120.4 (C-12), 120.1 (2C; C-30, C-32), 119.6 (2C; C-
37, C-39), 114.5 (C-23), 100.6 (C-15), 60.1 (C-8), 56.5 (C-2), 55.6 (C-21),
42.2 (C-6), 39.7 (C-3), 27.6 (C-5), 27.4 (C-4), 24.7 (C-7). 31P NMR (243
MHz, CDCl3, 258C): d (ppm) –11.78.
and refined on F2 by
a full-matrix least-squares technique using
SHELXL-9737 with anisotropic thermal parameters for non-H atoms.
Dichloromethane molecule lies on a twofold axis and therefore its s.o.f.
is 0.5. All H atoms were found in difference Fourier maps. In the final
refinement cycles, they were treated as riding atoms in geometrically
9-O-Diethylphosphorylquinine (2b)41
˚
˚
optimized positions, with NÀÀH 5 0.93 A and CÀÀH 5 0.95–1.00 A, and
White solid, yield 56%, m.p. 108-1108C. HRMS (TOF MS ESI): m/z
calcd for C24H34N2O5P1: 461.2206 [M1H]1; found: 461.2202. 1H NMR
with Uiso(H) 5 1.2Ueq(N,C) for NH, CH and CH2, or 1.5Ueq(C) for CH3.
Chirality DOI 10.1002/chir

´
GORECKI ET AL.
320
3
(600 MHz, CDCl3, 258C): d (ppm) 8.79 (d, JH,H 5 4.4 Hz, 1H; H-2), 8.05
(d, 3JH,H 5 9.2 Hz, 1H; H-8), 7.46 (br, 2H; H-3, H-5), 7.40 (dd, 4JH,H 5 2.6
3
Hz, JH,H 5 9.2 Hz, 1H; H-7), 5.99 (br, 1H; H-11), 5.87 (m, 1H; H-20),
3
5.03 (m, 2H; H-21), 4.10 (m, JH,H 5 7.1 Hz, 1H; H-23a), 3.96 (m, 4H;
OCH3, H-23b), 3.71 (br, 2H; H-23’), 3.38 (br, 1H; H-12), 3.18 (br, 1H; H-
18’), 3.02 (br, 1H; H-14’), 2.64 (br, 1H; H-18), 2.60 (br, 1H; H-14), 2.29
(br, 1H; H-15), 2.00 (br, 1H; H-17), 1.91 (br, 1H; H-16), 1.76 (br, 2H; H-
3
19’, H-17’), 1.56 (br, 1H; H-19), 1.23 (t, JH,H 5 7.0 Hz, 3H; H-24), 0.93
(br, 3H; H-24’). 13C NMR (151 MHz, CDCl3, 258C): d (ppm) 157.9 (C-
16), 147.4 (C-11), 144.8 (C-13), 143.6 (C-19), 141.8 (C-22), 131.8 (C-18),
126.8 (C-14), 121.9 (C-17), 118.6 (C-12), 114.5 (C-23), 101.2 (C-15), 63.9
(2JC,P 5 6.0 Hz; C-28), 63.8 (2JC,P 5 6.0 Hz; C-31), 60.3 (C-8), 56.5 (C-2),
55.7 (C-21), 42.3 (C-6), 39.8 (C-3), 27.7 (C-5), 27.5 (C-4), 24.6 (C-7), 16.0
(3JC,P 5 7.6 Hz; C-29), 15.7 (3JC,P 5 7.6 Hz; C-32). 31P NMR (243 MHz,
CDCl3, 258C): d (ppm) –1.32.
9-O-Diphenylphosphorylquinine Hydrochloride (2a3HCl)
Pale yellow solid, m.p. 112-1138C. 1H NMR (600 MHz, CDCl3, 258C): d
3
(ppm) 13.77 (br, 1H; NH1), 8.67 (s, 1H; H-2), 8.59 (d, JH,H 5 9.0 Hz,
3
1H; H-8), 8.26 (s, 1H; H-5), 7.84 (d, JH,P 5 6.6 Hz, 1H; H-11), 7.78 (s,
1H; H-3), 7.64 (dd, 4JH,H 5 1.1 Hz, 3JH,H 5 9.0 Hz, 1H; H-7), 7.32 (m, 4H;
2H o-Ph, 2H m-Ph), 7.26 (m, 2H; o-Ph’), 7.22 (t, 1H; p-Ph), 7.15 (m, 3H;
1H p-Ph’, 2H m-Ph’), 5.73 (m, 1H; H-20), 5.12 (m, 2H; H-21), 4.28 (s, 3H;
OCH3), 4.01 (br, 1H; H-18’), 3.58 (br, 1H; H-12), 3.56 (m, 1H; H-14’), 3.25
(m, 2H; H-18, H-14), 2.80 (br, 1H; H-15), 2.25 (br, 2H; H-16, H-17’), 2.09
(br, 1H; H-19’), 1.98 (br, 1H; H-19), 1.92 (br, 1H; H-17). 13C NMR (151
2
MHz, CDCl3, 258C): d (ppm) 162.2 (C-16), 149.9 (d, JC,P 5 7.6 Hz; C-
28), 149.9 (d, JC,P 5 6.0 Hz; C-35), 149.2 (C-13), 138.2 (C-11), 136.7 (C-
2
Fig. 1. Synthesis and proton numbering of phosphorylated quinines 2.
22), 134.5 (C-19), 130.2 (2C; C-29, C-33), 130.1 (2C; C-36, C-40), 129.2 (C-
14), 127.8 (C-17), 126.2 (C-31), 126.1 (C-38), 123.9 (C-18), 120.0 (C-30),
119.9 (C-32), 119.6 (C-37), 119.6 (C-39), 119.3 (C-12), 118.05 (C-23),
102.2 (C-15), 73.3 (C-9), 59.1 (C-8), 59.0 (C-21), 54.9 (C-2), 43.0 (C-6),
36.8 (C-3), 26.7 (C-4), 24.2 (C-5), 19.1 (C-7). 31P NMR (243 MHz, CDCl3,
258C): d (ppm) –14.27.
involved in host-guest binding: charge assisted hydrogen
bonding between the carboxylic group of the amino acid and
the receptor tertiary amine, hydrogen bonding between the
amide hydrogen and one of the oxygen atoms of the phos-
phate and lipophilic or p-p stacking interactions. Importantly,
the designed molecules were readily available on a multi-
gram scale through a one step synthesis starting from qui-
nine (Fig. 1). Phosphorylation of this substrate with either di-
phenyl- or diethylchlorophosphate in the presence of potas-
sium tert-butoxide allowed us to obtain products 2a and 2b
in satisfactory yields (66% and 56%, respectively).
9-O-Diethylphosphorylquinine Hydrochloride (2b3HCl)
Pale yellow solid, m.p. 160-1618C. 1H NMR (600 MHz, CDCl3, 258C): d
3
(ppm) 13.74 (br, 1H; NH1), 8.80 (d, JH,H 5 4.8 Hz, 1H; H-2), 8.06 (d,
3
3JH,H 5 9.6 Hz, 1H; H-8), 7.81 (br, 1H; H-5), 7.58 (d, JH,H 5 4.2 Hz, 1H;
4
3
3
H-3), 7.46 (dd, JH,H 5 2.4 Hz, JH,H 5 9.6 Hz, 1H; H-7), 7.18 (d, JH,H
6 Hz, 1H; H-11), 5.63 (m, 1H; H-20), 5.10 (m, 2H; H-21), 4.29 (m, 3JH,H
5
5
7.9 Hz, 2H; H-23), 4.22 (s, 3H; OCH3), 4.16 (br, 1H; H-18’), 4.04 (m, 3JH,H
5 7.2 Hz, 1H; H-23’a), 3.82 (m, JH,H 5 7.8 Hz, 1H; H-23’b), 3.50 (t, 1H;
3
Enantiodiscrimination in 1H NMR
H-14’), 3.43 (br, 1H; H-12), 3.19 (br, 1H; H-18), 3.17 (br, 1H; H-14), 2.77
(br, 1H; H-15), 2.25 (br, 2H; H-17’, H-19’), 2.19 (br, 1H; H-16), 1.96 (br,
1H; H-19), 1.66 (t, 1H; H-17), 1.43 (t, JH,H 5 7.2 Hz, 3H; H-24), 1.02 (t,
3
The chiral discriminating potency of novel receptors 2 was
tested with the use of a set of ligands possessing different
functional groups, namely amino acids, carboxylic acids,
amines and alcohols (compounds 3, Fig. 2). In most cases,
both free and protected forms of these analytes were studied.
3,5-Dinitrobenzoyl (DNB) derivatives were used, as the pres-
ence of this protecting group enhanced interactions with the
electron rich quinoline fragment of the receptor.24 Moreover,
the resonances of the protons of the 3,5-dinitrophenyl ring
3JH,H 5 7.2 Hz, 3H; H-24’). 13C NMR (151 MHz, CDCl3, 258C): d (ppm)
159.7 (C-16), 146.6 (C-11), 144.7 (C-13), 140.1 (C-19), 136.9 (C-22), 131.8
(C-18), 125.6 (C-14), 123.8 (C-17), 118.5 (C-12), 117.7 (C-23), 100.8 (C-
15), 72.8 (C-9), 65.2 (2JC,P 5 5.6 Hz; C-28), 65.1 (2JC,P 5 5.6 Hz; C-31),
59.4 (C-8), 58.2 (C-21), 54.9 (C-2), 42.9 (C-6), 36.9 (C-3), 26.9 (C-4), 24.2
(C-5), 18.8 (C-7), 16.3 (3JC,P 5 6.3 Hz; C-29), 15.8 (3JC,P 5 6.6 Hz; C-32).
31P NMR (243 MHz, CDCl3, 258C): d (ppm) –3.27.
1
RESULTS AND DISCUSSION
Design and Synthesis
were low-frequency-shifted in the H NMR spectrum, which
made them a simple and indicative tool for enantiomeric
composition analysis.
Although native and modified quinines have been widely
studied for stereoselective applications, the organophospho-
rus derivatives remain unexplored in this respect. In this
work, we envisaged substitution of the hydroxyl group in
quinine with a phosphate diester moiety to construct novel
chiral receptors for N-substituted amino acids. The spatial
arrangement of three molecular fragments, the tertiary bicy-
clic amine (quinuclidine), heteroaromatic system (quinoline)
and additional phosphate triester group, provided the possi-
ble formation of a cavity that could specifically interact with a
variety of ligands. Three types of interactions could be
CSAs can undergo fast, intermediate or slow exchange
with their ligands. In the first case, the NMR spectrum is a
weighted average of the bound and unbound ligand and
presents two sets of signals derived from the R and S enan-
tiomers. If enantiomeric discrimination occurs under slow
exchange conditions, three signal sets are observed: one for
the unbound guest compound and two for each enantiomer
bound with the receptor.42 According to the theory, fast
exchange stereoselective recognition of enantiomers by
CSAs occurs when the transient diastereomeric complexes
Chirality DOI 10.1002/chir

TUNING THE ENANTIODISCRIMINATION POTENCY OF QUININE
321
Fig. 2. Structures of the studied ligands.
are characterized by different stereochemical arrangements
and/or different association constants. Thus, the concentra-
tion of both the selector and selectand); as well as the tem-
perature of the solution may significantly influence the enan-
tiodiscrimination efficiency. The latter factor causes altera-
tion in the association constants and degree of
conformational homogeneity of complexes.42 In this context,
a 50 mM concentration (1:1 molar ratio, Supporting Informa-
tion Table S1) and a temperature of 283 K (Supporting Infor-
mation Fig. S1) were chosen as optimal for routine analysis
(E).
The studied ligands could be formally divided into four
subclasses with respect to the ligand-receptor interactions
influencing the enantiodifferentiation efficiency. The first
one, N-DNB amino acids (compounds 3a-c), exhibited the
highest values of Dd among all of the explored compounds
(a range of 0.1187–0.2320 ppm for the amide protons and
0.0873–0.1979 ppm for the DNB para proton). Effective com-
plexation of the DNB-protected amino acids might be associ-
ated with three possible intermolecular interactions: a)
charge-assisted hydrogen bonding between the carboxylic
moiety of the ligand and protonated amine group of the
receptor quinuclidine fragment; b) hydrogen bonding
between the amide NH of the DNB amino acid and OH of 1
or oxygen atom of the phosphate moiety of 2; and c) p-stack-
ing interactions between the electron poor DNB group and
electron rich quinoline ring of the receptor molecule. Within
the second subclass of ligands, DNB amino acid methyl
esters (compounds 3d-f), medium enantiodiscrimination effi-
ciency was observed (Dd in the range of 0.0122–0.0526 ppm
for the NH proton and 0.0031–0.0194 ppm for the DNB para
proton). The structure of 3d-f offers only two possible inter-
actions with the host molecule, namely hydrogen bonding
and p-stacking what explains the diminished values of chemi-
Chirality DOI 10.1002/chir

´
GORECKI ET AL.
322
TABLE 1. Enantiodifferentiation efficiency of native (1) and
with respect to their enantiodiscrimination efficiency. In gen-
eral, the phosphorylated hosts appeared to be privileged with
respect to native quinine, and this was general across all
three groups of amino acid derivatives (3a-h). Interestingly,
phosphorylated quinines (2), expressed as the chemical shift
nonequivalences (Dd) observed by 1H NMR for racemic mix-
tures of ligands 3 in the presence of the hosts measured under
optimized conditions (50:50 mM ratio, 283 K)
1
different patterns of H resonance differentiation upon com-
plexation with 2a and 2b were observed for the N-DNB free
acids (3a-c). The diphenyl phosphate derivative (2a) showed
the greatest influence on the Dd of the ligand amide proton,
whereas the diethyl phosphate derivative (2b) had the great-
est influence on the Dd of the aromatic protons of the N-pro-
tecting group. As expected, the hydrochloride salt 2b3HCl
lost the efficiency of the corresponding nonprotonated amine
because of an alteration of the host-guest ion pair formation.
For practical applications, 2b is recommended, as it differen-
tiated enantiomers the most clearly through low-frequency-
Dd (ppm)
Ligand
Proton
1
2a
2b
2b 3 HCl
3a
o-H
p-H
NH
CHa
CH3
o-H
p-H
NH
CHa
CH3
CH3
o-H
p-H
NH
CHa
o-H
p-H
0.037
0.031a
0.124
0.036
0.016
0.006
0.028
0.106
0.073
0.029
0.027
0.014a
0.012a
0.081
–
0.023
0.035
0.232
0.020
0.023
0.042
0.073
0.119
0.044a
0.010
0.004
–
0.115a
0.189a
0.101
0.155
0.030
0.107
0.198
0.094
0.121
0.003
0.007
0.075
0.087
ꢀ 0.119
0.038
–
0.004
0.053
0.006
0.002
0.012
0.004
0.016
0.038
0.034
0.031
0.037
0.029
–
0.025
0.022
–
3b
1
shifted resonances in a noncrowded region of the H spec-
trum (as exemplified in Fig. 3).
–
–
–
For the group of methyl esters (3d-f), the discrimination
properties of all quinine derivatives was significantly
decreased, particularly in the case of the native one, due to
the loss of ion pairing. The highest values of Dd were
observed for the amide guest proton upon complexation with
2b. It is worth noting that the same receptor in the form of
its hydrochloride salt (2b3HCl) was quite effective, induc-
ing particularly high Dd values for the DNB aromatic protons
(poorly separated by the other selectors). These observa-
tions could be explained by a difference in the number of
potential hydrogen bonds formed in the complex. For the
nonprotonated forms, only one such specific contact can be
formed, whereas in the case of 2b3HCl, there is the possi-
bility of additional bonding where the quaternary ammonium
group can serve as the donor. N-Cbz substitution of the
amino acids resulted in a group of compounds that produced
moderate chemical shift nonequivalences with hosts 1, 2a
and 2b, and a lack of enantiodiscrimination for the hydro-
chloride of 2b. For the final set of monofunctionalized com-
pounds (3i-n), the studied effect was less significant and
irregularly depended on the kind and state (protected or not)
of the heteroatom moiety present in their structure. Thus,
the DNB protected amine 3i and alcohol 3j enantiomers
were the most efficiently distinguished by 2b3HCl, with effi-
ciency similar to the DNB amino acid methyl esters. On the
3c
3d
0.010
0.008
–
0.005
0.014
0.016
–
0.002
0.004
0.003
0.014
0.019
0.021
0.031
0.168
0.079
–
–
–
–
–
–
NH
0.036
0.002
0.003
0.013
0.003
0.003
0.032
0.003
0.006
0.015
–
CHa
OMe
CH3
o-H
p-H
NH
OMe
CH3
CH3
p-H
CHa
NH
0.002
–
–
3e
–
0.007
0.002
–
–
–
0.003
–
–
0.079
0.018
0.040
0.006
0.020
–
0.003
0.002
a
a
a
a
3f
–
0.003
0.005
0.003
–
–
0.004
0.012
0.044
3g
3h
3i
CHa
NH
0.040
–
–
a
0.044
a
a
CH3
CHa
CH3
CH3
o-H
–
0.042a
0.018
0.016
–
0.036
0.006
0.003
0.002
0.006
–
–
–
–
0.004
0.004
0.002
0.001
–
p-H
0.003
–
–
–
–
–
–
CH3
CH3
–
CH3
CHCH3
CH2CH3
CHa
3j
3k
3l
–
–
–
0.007
0.032
0.013
0.033
0.003
0.004
0.001
0.010a
0.002
0.006
–
–
3m
0.002
–
0.005
3n
0.003
aOverlapping signals.
cal shift nonequivalence in comparison to the free acids. The
loss in enantioselective efficiency of N-benzyloxycarbonyl
protected amino acids (compounds 3g and 3h) probably
resulted from weaker lipophilic interactions of the receptor
with the phenyl ring of the Cbz-protecting group than with
the significantly electron-poorer DNB fragment. The remain-
ing compounds (3i-3n) exhibited the lowest enantiodiscrimi-
nation which was likely the result of a limited number of
potential contacts.
The results presented in Table 1 allowed a comprehensive
comparison between the modified and nonmodified quinines
Fig. 3. Selected resonances of the racemic mixture (a) and S enantiomer
(b) of 3b in 1H NMR spectra in the presence of 2b (50:50 mM ratio, 283 K).
Chirality DOI 10.1002/chir

TUNING THE ENANTIODISCRIMINATION POTENCY OF QUININE
323
centration (10 mM). At this concentration, no precipitation of
the substrate or complex occurred. The ligand concentration
was finally adjusted at 5.0 mM at a host-guest ratio of 1:2,
which ensured complete ligand binding and thus reliable
enantiomer composition analysis.
Four different patterns in the 31P NMR spectra were
observed (Table 2). The most preferred case for analysis was
found for N-substituted amino acids (3a, 3b, 3g and 3h)
and 2-phenylpropionic acid (3n). Here, proton transfer
between the carboxylic acid and amine must have occurred,
and the ion pairing and other interactions were apparently
strong enough to reach slow exchange conditions on the
NMR time scale at the applied temperature of 180 K. As a
result, the 31P NMR spectra revealed signals derived from
two nonbound excess 2b conformers (–1.26 ppm, –1.42
ppm), a novel one originating from its protonated form
(–2.31 ppm) and those resulting from 2b complexed with the
ligand enantiomers. For complexes of 2b with N-benzyloxy-
carbonylamino acids 3g and 3h, each enantiomer showed
two 31P resonances (one significantly predominated, Figs.
4b–4d and Table 2), while the complexes of enantiomers of
the DNB derivatives 3a and 3b showed one or two signals.
Phenylpropionic acid (3n) represented the simplest instance,
as each stereoisomer formed a complex producing one
signal.
In the case of compound 3m, apart from the free and pro-
tonated 2b signals, just one novel resonance was registered,
and it did not depend on the enantiomeric composition. The
observed peak broadening could suggest that the spectra
were recorded under medium exchange conditions. This
would result from the ligand-receptor interactions being too
weak to achieve slow exchange under the experimental con-
ditions (180 K).
For the complexation of 2b with DNB-amino esters (3d-f),
1-phenylethylamine (3i) and nonprotected 1-phenylethanol
(3l), a high frequency shift of both conformer resonances
was detected that represented a weighted average of bound
and unbound quinine. For the remaining compounds (3j and
Fig. 4. Frozen conformational equilibrium of 2b and the enantiodifferen-
tiation effect under slow exchange conditions illustrated by the 31P NMR
spectra of the free selector (a) and its complexes with racemic (b) and enan-
tiomerically pure (c and d) Cbz-Ala ligand (3g) (10:5 mM ratio, 180 K).
other hand, nonfunctionalized quinine was the compound of
choice for carboxylic acids (3m and 3n), which is in agree-
ment with the literature data.25 This CSA also gave the high-
est Dd value for racemic phenylethanol (3l). In summary,
except for the last three mentioned cases, the novel phospho-
rus quinines appear to be superior CSAs compared to the
nonmodified ones.
TABLE 2. 31P NMR chemical shifts (d) observed for 2b in the
presence of racemic mixtures of the analyzed ligands 3 at 180
K (10:5 mM ratio) and the percentage of each conformer in
parentheses. Entries indicating medium or fast exchange
conditions between complexed and free quinine 2b are
marked in italics
Enantiodiscrimination in 31P NMR
Using the presence of a phosphorus atom as the character-
istic feature of the novel compounds, the enantiodifferentia-
tion phenomenon could also be studied by means of 31P
NMR. Phosphorus resonance spectra are much more
straightforward for interpretation in comparison to proton
spectra. However, no discrimination effect was observed in
preliminary experiments at room temperature because of fast
exchange between host molecules unbound and bound with
the ligands. To achieve slow exchange conditions and to elu-
cidate the 31P NMR resonances derived from the R and S
enantiomers complexed with the CSA, the temperature of
the experiments was decreased to 180 K. The spectrum of
phosphorylated receptor 2b acquired under such conditions
revealed resonances of particular conformations, with two
predominating (Fig. 4a).
d (ppm)
Ligand
2b3S-ligand
2b 3 R-ligand
3a
3b
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
–1.08
–2.41 (84%); –2.59 (16%)
–2.50
–0.84 (59%); –2.41 (41%)
–1.53 (25%); –2.44 (75%)
–1.53 (26%); –2.57 (74%)
–1.53 (25%); –2.44 (75%)
–2.21 (91%); –2.46 (9%)
–2.16 (93%); –2.49 (7%)
–2.43 (85%); –2.50 (15%)
–2.50a
–1.77 (26%); –2.32 (74%)
No interaction
No interaction
–1.29 (24%); –1.49 (76%)
–2.14
Subsequently, the conditions of the low temperature
experiments were optimized using the selected ligand (3h)
by changing its concentration at a constant host (2b) con-
–2.14
–2.22
aTwo signals overlapping.
Chirality DOI 10.1002/chir

´
GORECKI ET AL.
324
Fig. 5. 1H NMR (a) and 1D ROESY (b-e) spectra of 2b at 200 K, with the protons important for conformational analysis (H3 and H5 of both conformers) irradi-
ated. * – signals derived from the less populated conformation.
3k), no specific host-guest complex resonances were
observed.
conformation in solution.2,44 In NMR studies on chiral recog-
nition phenomena, this arrangement is considered to be
responsible for its enantiodiscrimination abilities, as the
unhindered quinuclidine nitrogen is able to form strong
interactions with analytes.
Conformational Analysis of Phosphorylated Quinines
The conformation of the chiral selector is of a great impor-
tance to its enantiodiscriminating properties, as it determines
the functionality and size of the binding site. Therefore, the
conformations of CSAs 2, in their free and protonated forms
(the later resembling a state formed upon complexation of an
acid), were studied by means of selective 1D and 2D ROESY
experiments. The stereochemistry of quinine and its deriva-
tives can be described in term of rotations around the C8-C9
and C9-C13 bonds. It has previously been established that
cinchona alkaloids can, in principle, adopt four different con-
formations, two open and two closed (Supporting Information
Fig. S2).26,43 In the open states, the quinuclidine nitrogen
atom is situated remotely from the quinoline ring, while in
the closed conformers, it points toward the quinoline ring.
Thus, intramolecular ROEs between the quinoline H17 and
H18 protons and quinuclidine H3 and H5 protons, along with
ROEs involving H11 and H12, are the most diagnostic tools
for identification of the rotamers. The different conforma-
tional states involve changes in the H11-C9-C8-H12 dihedral
Conformational studies of phosphorylated quinine deriva-
tives 2a and 2b were difficult to perform at room tempera-
1
ture, as the H NMR spectra showed significant broadening
1
of a majority of the H resonances. This included the signal
of proton H11, key for conformational analysis, which was
almost flattened. Moreover, the quinuclidine H3 and H5
resonances overlapped in the spectrum of 2b. Thus, the tem-
perature of the experiments was decreased to 200 K to
achieve slow exchange conditions and allow for reliable anal-
ysis of the existing conformational arrangement. The 1H
NMR spectrum of 2b revealed two frozen rotational states
present in a 73:27 ratio (Fig. 5a). This observation was well
correlated with the 31P NMR spectrum, which showed two
resonances (73:27 molar ratio) at –1.42 ppm and –1.26 ppm,
respectively.
ROEs H5-H11, H5-H18 and H3-H12, characteristic of
closed conformation 2, were detected for the more populated
species in the 1D ROESY spectra (Fig. 5). In the case of the
minor rotamer, the presence of intense H3*-H11*, H3*-H18’*
and H5*-H12* contacts indicated the closed conformation 1.
3
angle, which is reflected in the values of the JH11,H12 cou-
pling constants measured in the NMR spectra. It has been
reported in the literature that parent quinine prefers an open
3
Unfortunately, the vicinal coupling JH11,H12 values were not
Chirality DOI 10.1002/chir

TUNING THE ENANTIODISCRIMINATION POTENCY OF QUININE
325
less populated one; these values are characteristic of closed
arrangements. Their existence was also evident by compari-
son of the H11-H18’ and H11-H12 ROEs, for which the for-
mer was more intense than the latter (Supporting Informa-
tion Fig. S3). In the case of the less populated species, the
presence of the ROEs H3*-H18’* and H3*-H11* confirmed
the existence of closed conformer 1. Because of signal over-
lap of the quinoline and phenyl protons, interactions charac-
teristic of closed conformation 2, including those originating
from the H5 proton, were undetectable. However, the major
closed conformer 2 was indicated by the H11 and H5 ROE
3
and vicinal coupling constants JH11,H12 5 8.5 Hz. The struc-
tures of the conformers of 2a modeled based on the NMR
data (Supporting Information Figs. S4a and S4b) were similar
to those found for 2b. In summary, both phosphorylated qui-
nines 2a and 2b adopt two closed conformations, with form
2 predominating.
Regarding the diphenyl and diethyl ester moieties, no
dipolar interactions with the quinoline or quinuclidine pro-
tons of 2a and 2b were detected in the 1D and 2D ROESY
experiments (curried out at 200 K as well as at 298 and 283
K at a spin lock time of 100–1200 ms). This indicated that
the organophosphorus fragments are located externally to
the alkaloid core.
Protonation of quinine derivatives 2a and 2b significantly
changes their conformational status. The ROE effects pro-
tons H3-H17’ and H11-H5 detected for 2b3HCl clearly indi-
cated the presence of open conformer 3. This was further
supported by the stronger interaction of H11 with H12 when
compared to H11-H18’ (Fig. 7). The corresponding ROEs, in-
dicative of open conformation 3, were also present in
2a3HCl (Supporting Information Fig. S5). Finally, the pres-
ence of the open conformation of both protonated quinines
was supported by loss of the 3JH11,H12 in comparison with the
values of the corresponding coupling constant in their free
forms.
The presence of an intramolecular hydrogen bond
between the NH and phosphate moiety, which stabilizes
open conformation 3, was confirmed in the modeled struc-
tures of both protonated 2a and 2b (Supporting Information
Figs. S4c and S6c, respectively).
The architecture, to some extent complementary to the
NMR data, was established for the solid state structure of
2b3HCl dichloromethane hemisolvate, which was deter-
mined by single-crystal X-ray diffraction analysis (Fig. 8 and
Supporting Information Table S2). The adopted open confor-
mation 3 of 2bH1 (similar to that of quininium cation found
in its crystalline derivatives)45–48 showed intramolecular dis-
˚
tances of H3-H17’ and H5-H11 equal to 2.25 and 2.09 A,
respectively. The arrangement of the three structural parts
(quinoline, quinuclidine and phosphate ester) formed a cav-
ity where a chlorine ion and partially a molecule of solvent
(dichloromethane) were located. However, in this case, the
positively charged amine group formed the ion pair with
chlorine (Fig. 8 and Supporting Information Table S3), in
contrast to the NH-phosphate contact modeled in solution.
Fig. 6. Conformations of phosphorylated quinine derivative 2b (minor –
closed 1 and major – closed 2, panels a and b, respectively) and its hydro-
chloride 2b3HCl (open 3, panel c) modeled based on the 1D ROESY experi-
ments. Indicative interproton contacts are marked as solid green lines.
[Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
determined because of signal overlap. Using interproton con-
tacts obtained from NMR studies, the structures of both 2b
conformers were modeled (Figs. 6a and 6b).
Conformational Analysis of Complexes of N-Cbz-Leucine
(3h) with 2b
Analogous to 2b, the diphenyl ester was present in a 68:32
ratio (31P NMR d –10.64 ppm and –11.08 ppm, respectively).
The measured vicinal coupling constants 3JH11,H12 were equal
to 8.5 Hz for the predominating rotamer and 10.3 Hz for the
Because the conformational changes of chiral selectors
upon analyte binding are crucial for understanding of the chi-
ral recognition process, selected diastereomeric complexes
(3h32b) were investigated in detail. For R-3h32b, the
Chirality DOI 10.1002/chir

´
GORECKI ET AL.
326
Fig. 7. 1H NMR (a) and 1D ROESY (b-d) spectra of 2b3HCl at 200 K, with the protons important for conformational analysis (H3, H5 and H11) irradiated.
presence of ROEs H3-H17’ and H5-H11, along with H11-H12
being more pronounced than H11-H18’, indicated open con-
formation 3 (Supporting Information Fig. S6). The situation
was less clear for the opposite enantiomer because the H3
and H5 protons were superimposed (Supporting Information
Fig. S7). Nevertheless, the ROE involving proton H17’ sug-
gested the presence of the open 3 or open 4 form. The mod-
eling studies (see below) favored the former option. Thus,
2b interacts with each enantiomer of 3h, changing its native
conformation into open 3, which corresponds well with that
adopted by the protonated form 2b3HCl.
Because the ROESY experiments did not show intermolec-
ular contacts, complexation-induced shifts of selector 2b pro-
tons upon the binding of either R-3h or S-3h were assessed
to gain insight into the interactions. To exclude the chemical
shift changes resulting from conformational changes upon
protonation, the values measured for 2b3HCl were sub-
tracted from those registered for 3h32b (Fig. 9).
Fig. 8. Molecular structure of 2b3HCl30.5CH2Cl2 (with the atom-num-
bering scheme) joined via charge-assisted N–H. . .Cl hydrogen bond (H. . .Cl
2.09 A, N. . .Cl 3.022(3) A, N–H. . .Cl 1778; dashed line) with Cl2 in the crystal
˚
˚
of (C24H34N2O5P1)Cl230.5CH2Cl2. Intramolecular C–H. . .O contact (H. . .O
˚
˚
2.46 A, C. . .O 3.406(4) A, C–H. . .O 1618) is also shown. Displacement ellip-
soids represent the 40% probability level. [Color figure can be viewed in the
online issue, which is available at wileyonlinelibrary.com.]
Fig. 9. Differences between the chemical shifts of the complexed quinine
receptor and its protonated form: S-3h32b – 2b3HCl and R-3h32b –
2b3HCl.
Chirality DOI 10.1002/chir

TUNING THE ENANTIODISCRIMINATION POTENCY OF QUININE
327
CONCLUSIONS
The structural and functional elements of the quinine mol-
ecule are assembled in a unique, characteristic three-dimen-
sional arrangement that makes this compound exceptionally
useful in stereoselective applications. Additionally, the pres-
ence of reactive groups allows further development/modifi-
cation of the native compound to adjust its properties. Trans-
formations of the C-9 hydroxyl group to esters or carba-
mates, described in the literature seem to be the most
common synthetic approaches to new compounds in this se-
ries. In this respect, we envisaged and validated phosphoryl-
ated quinines as effective CSAs. These compounds induced
1
chemical shift nonequivalences of the H and 31P NMR sig-
nals in a set of racemic analytes. Diethyl and diphenyl phos-
phate derivatives showed a high degree of complementarity
for protected amino acids and outdistanced the native qui-
nine action in this respect, which confirmed our design
1
approach. The proposed protocol based on H NMR can be
considered an alternative for the routine analysis of enan-
tiomer composition. The enantiodiscrimination effect was
rationalized in terms of molecular interactions between the
host and guest molecules. The NMR data and modeling stud-
ies defined the polar contacts as the major forces responsible
for the ligand affinity for the receptors, with essential partici-
pation of the phosphate group. Conformational rearrange-
ment involving a switch from a closed to an open species fur-
ther illustrated the process of adduct formation.
As the quinine phosphates are readily prepared, other ste-
reoselective applications, such as enantioselective catalysis
or chiral separation techniques can be easily foreseen as a
continuation of these studies. Furthermore, the phosphorus
moiety offers possibilities in terms of subsequent transforma-
tions, such as selective and exhaustive hydrolysis and trans-
esterification of the phenyl groups. Such features make the
described quinine derivatives promising and versatile chiral
discriminators of general relevance.
Fig. 10. Models of the S-3h32b and R-3h32b complexes (panels a and
b, respectively). The molecular surface of the receptor was colored according
to interpolated charge. Hydrogen bonds are marked as green solid lines. Pro-
tons showing high complexation-induced shifts (H5, H11, H14, H18’) are
marked as white spheres. [Color figure can be viewed in the online issue,
which is available at wileyonlinelibrary.com.]
ACKNOWLEDGMENTS
Calculations were performed using the software resources
from the Wroclaw Centre for Networking and Supercomputing.
LITERATURE CITED
1. Yoon TP, Jacobsen EN. Privileged chiral catalysts. Science
2003;299:1691–1693.
The overall patterns of complexation-induced shifts were
similar to each other for both complexes. The highest abso-
lute values were observed for H11, H14, and H18’ if consider-
ing the aliphatic part and H5 for the aromatic portion. These
protons are located inside the cavity formed by the host mol-
ecule in open conformation 3. Using an NMR data-based
model (Fig. 10), a charge assisted hydrogen bond between
the ligand carboxylic group and protonated 2b amine moiety
as well as a hydrogen bond between the phosphate oxygen
atom of 2b and the NH of 3h were found to be crucial stabi-
lizing forces of the complex. Significantly, the phosphate
group appeared to be essential for effective complexation
and enantiodiscrimination in comparison to the native qui-
nine. When comparing enantiomer binding, it is clear that
the Ha proton of the ligands significantly changes in terms of
chemical environment. It is pointed toward the cavity for the
S stereoisomer and exposed to the solvent for the R enan-
tiomer. Such a difference can reflect in the high enantiodis-
crimination (Dd) observed for this proton (Table 1).
2. Uccello-Barretta G, Balzano F, Quintavalli C, Salvadori P. Different enan-
tioselective interaction pathways induced by derivatized quinines. J Org
Chem 2000;65:3596–3602.
3. Maier NM, Schefzick S, Lombardo GM, Feliz M, Rissanen K, Lindner W,
Lipkowitz KB. Elucidation of the chiral recognition mechanism of Cin-
chona alkaloid carbamate-type receptors for 3,5-dinitrobenzoyl amino
acids. J Am Chem Soc 2002;124:8611–8629.
4. Czerwenka C, Zhang MM, Ka¨hlig H, Maier NM, Lipkowitz KB, Lindner
W. Chiral recognition of peptide enantiomers by Cinchona alkaloid
derived chiral selectors: mechanistic investigations by liquid chromatog-
raphy, NMR spectroscopy, and molecular modeling.
2003;68:315–8327.
J Org Chem
5. Uccello-Barretta G, Balzano F, Salvadori P. Rationalization of the multire-
ceptorial character of chiral solvating agents based on quinine and its
derivatives: overview of selected NMR investigations. Chirality
2005;17:S243–S248.
6. Bicker W, Chiorescu I, Arion VB, La¨mmerhofer M, Lindner W. Contribu-
tions to chromatographic chiral recognition of permethrinic acid stereo-
isomers by a quinine carbamate chiral selector: evidence from X-ray dif-
fraction, DFT computations, 1H NMR, and thermodynamic studies. Tetra-
hedron: Asymmetry 2008;19:97–110.
Chirality DOI 10.1002/chir

´
328
GORECKI ET AL.
7. Uccello-Barretta G, Balzano F, Bardoni S, Vanni L, Giurato L, Guccione
26. Uccello-Barretta G, Vanni L, Balzano F. NMR enantiodiscrimination phe-
nomena by quinine C9-carbamates. Eur J Org Chem 2009;860–869.
S. Chiral discrimination processes by C9 carbamate derivatives of dihy-
droquinine: interaction mechanisms of diastereoisomeric 9-O-[(S)- or (R)-
1-(1-Naphthyl)ethylcarbamate]dihydroquinine and the two enantiomers
of N-(3,5-Dinitrobenzoyl)alanine methyl ester. Tetrahedron: Asymmetry
2008;19:1084–1093.
27. Uccello-Barretta G, Vanni L, Berni MG, Balzano F. NMR enantiodiscrimi-
nation by pentafluorophenylcarbamoyl derivatives of quinine: C10 versus
C9 derivatization. Chirality 2011;23:417–423.
28. Mlynarz P, Rudzinska E, Berlicki L, Kafarski P. Organophosphorus
supramolecular chemistry. Part 2. Organophosphorus receptors. Curr
Org Chem 2007;11:1593–1609.
´
8. Kacprzak K, Gawronski J. Cinchona alkaloids and their derivatives: versa-
tile catalysts and ligands in asymmetric synthesis. Synthesis 2001;961–998.
9. La¨mmerhofer M, Hebenstreit D, Gavioli E, Lindner W, Mucha A, Kafar-
ski P, Wieczorek P. High-performance liquid chromatographic enan-
tiomer separation and determination of absolute configurations of phos-
phinic acid analogues of dipeptides and their alpha-aminophosphinic acid
precursors. Tetrahedron-Asymmetry 2003;14:2557–2565.
29. Wenzel TJ, Chisholm CD. Using NMR spectroscopic methods to deter-
mine enantiomeric purity and assign absolute stereochemistry. Prog
Nucl Magn Reson Spectrosc 2011;59:1–63.
30. Harger MJP. Chemical shift non-equivalence of enantiomers in the pro-
ton magnetic resonance spectra of partly resolved phosphinothioic acids.
J Chem Soc Perkin Trans 2 1978;326–331.
10. La¨mmerhofer M. Chiral separations by capillary electromigration techni-
ques in nonaqueous media: II. enantioselective nonaqueous capillary
electrochromatography. J Chrom A 2005;1068:31–57.
31. Omelanczuk J, Mikolajczyk M. Chiral t-butylphenylphosphinothioic acid:
a useful chiral solvating agent for direct determination of enantiomeric
purity of alcohols, thiols, amines, diols, aminoalcohols and related com-
pounds. Tetrahedron: Asymmetry 1996;7:2687–2694.
11. Gu¨bitz G, Schmid MG. Advances in chiral separation using capillary elec-
tromigration techniques. Electrophoresis 2007;28:114–126.
12. La¨mmerhofer M. Chiral recognition by enantioselective liquid chroma-
tography: mechanisms and modern chiral stationary phases. J Chrom A
2010;1217:814–856.
32. Shapiro MJ, Archinal AE, Jarema MA. Chiral purity determination by pro-
ton NMR spectroscopy. Novel use of 1,1’-binaphthyl-2,2’-diylphosphoric
acid. J Org Chem 1989;54:5826–5828.
13. La¨mmerhofer M. Chiral separations by capillary electromigration techni-
ques in nonaqueous media: I. enantioselective nonaqueous capillary elec-
trophoresis. J Chrom A 2005;1068:3–30.
33. Ravard A, Crooks PA. Chiral purity determination of tobacco alkaloids
and nicotine-like compounds by 1H NMR spectroscopy in the presence of
1,1-binaphthyl-2,2-diylphosphoric acid. Chirality 1996;8:295–299.
14. Rosini C, Uccello-Barretta G, Pini D, Abete C, Salvadori P. Quinine: an
inexpensive chiral solvating agent for the determination of enantiomeric
composition of binaphthyl derivatives and alkylarylcarbinols by NMR
spectroscopy. J Org Chem 1988;53:4579–4581.
34. Lacour J, Hebbe-Viton V. Recent developments in chiral anion mediated
asymmetric chemistry. Chem Soc Rev 2003;32:373–382.
35. Lacour J, Moraleda D. Chiral anion-mediated asymmetric ion pairing
chemistry. Chem Commun 2009;7073–7089.
15. Salvadori P, Pini D, Rosini C, Bertucci C, Uccello-Barretta G. Chiral dis-
criminations with Cinchona alkaloids. Chirality 1992;4:43–49.
36. CrysAlis CCD and CrysAlis RED programs, Oxford Diffraction Ltd., Yarn-
ton, Oxfordshire, England, 2010.
16. Van Oeveren A, Menge W, Feringa BL. Enantioselective synthesis of fur-
ylalcohols by catalytic asymmetric addition of diethylzinc to furanalde-
hydes. Tetrahedron Lett 1989;30:6427–6430.
37. Sheldrick GM. A short history of SHELX. Acta Crystallogr 2008;A64:112–
122.
17. Uccello-Barretta G, Pini D, Mastantuono A, Salvadori P. Direct NMR
assay of enantiomeric purity of chiral b-hydroxy esters by using quinine
as chiral solvating agent. Tetrahedron: Asymmetry 1995;6:1965–1972.
38. XP. Version 5.1. Bruker AXS Inc., Madison, Wisconsin, USA, 1998.
39. Ronwin E. Optical activity and the direct method of acylation. J Org
Chem 1957;22:1180–1182.
18. Klein J, Hartenstein H, Sicker D. First discrimination of enantiomeric
cyclic hemiacetals and methyl acetals derived from hydroxamic acids
and lactams of Gramineae by means of 1H NMR using various chiral sol-
vating agents. Magn Reson Chem 1994;32:727–731.
40. Pirkle WH, Pochapsky TC. Chiral molecular recognition in small bimo-
lecular systems: a spectroscopic investigation into the nature of diastereo-
meric complexes. J Am Chem Soc 1987;109:5975–5982.
19. Abid M, To¨ro¨k B. Cinchona alkaloid induced chiral discrimination for the
determination of enantiomeric composition of alpha-trifluoromethylated-
hydroxyl compounds by 19F NMR spectroscopy. Tetrahedron: Asymme-
try 2005;16:1547–1555.
41. Gazaliev AM, Balitskii SN, Fazylov SD, Kasenov RZ. Reaction of quinine
with dialkyl phosphites in conditions of interphase catalysis. Zh Obshch
Khim 1991;61:2365–2366.
42. Wenzel TJ, Hudson RH. Discrimination of chiral compounds using NMR
spectroscopy. Hoboken, New Jersey: Wiley; 2007.
20. Zymanczyk-Duda E, Skwarczynski M, Lejczak B, Kafarski P. Accurate
assay of enantiopurity of 1-hydroxy- and 2-hydroxyalklphosphonates
esters. Tetrahedron: Asymmetry 1996;7:1277–1280.
43. Bu¨rgi T, Baiker A. Conformational behavior of Cinchonidine in different
solvents: a combined NMR and ab initio investigation. J Am Chem Soc
1998;120:12920–12926.
21. Maly A, Lejczak B, Kafarski P. Quinine as chiral discriminator for deter-
mination of enantiomeric excess of diethyl 1,2-dihydroxyalkanephospho-
nates. Tetrahedron: Asymmetry 2003;14:1019–1024.
44. Reeder J, Castro PP, Knobler CB, Martinborough E, Owens L, Diederich
F. Chiral recognition of Cinchona alkaloids at the minor and major
grooves of 1,1’-binaphthyl receptors. J Org Chem 1994;59:3151–3160.
22. Rudzinska E, Berlicki L, Kafarski P, La¨mmerhofer M, Mucha A, Cin-
chona alkaloids as privileged chiral solvating agents for enantiodiscrimi-
nation of N-protected aminoalkanephosphonates—a comparative NMR
study. Tetrahedron Asymmetry 2009;20:2709–2714.
45. Oleksyn BJ, Serda P. Salt-bridge formation by Cinchona alkaloids: quini-
nium salicylate monohydrate. Acta Crystallogr 1993;B49:530–534.
46. Bhatt PM, Ravindra NV, Banerjee R, Desiraju GR. Saccharin as a salt for-
mer. Enhanced solubilities of saccharinates of active pharmaceutical
ingredients. Chem Commun 2005;1073–1075.
23. Klein J, Borsdorf R. NMR spectroscopic determination of enantiomers
via their triphenyltin derivatives: a new application of chiral solvating
agents. Fresenius J Anal Chem 1994;350:644–646.
47. Obaleye JA, Caira MR, Tella AC. Synthesis, characterization and crystal
structure of a polymeric zinc(II) complex containing the antimalarial qui-
nine as ligand. J Chem Crystallogr 2007;37:707–712.
24. Uccello-Barretta G, Bardoni S, Balzano F, Salvadori P. Versatile chiral
auxiliaries for NMR spectroscopy based on carbamoyl derivatives of dihy-
droquinine. Tetrahedron: Asymmetry 2001;12:2019–2023.
25. Uccello-Barretta G, Mirabella F, Balzano F, Salvadori P. C11 versus C9
carbamoylation of quinine: a new class of versatile polyfunctional chiral
solvating agents. Tetrahedron: Asymmetry 2003;14:1511–1516.
48. Mangwala Kimpende P, Van Meervelt L. Redetermination of
Bis{(1S,2S,4S,5R)-2-[(R)-hydroxy(6-methoxy-4-quinolyl)-methyl]-5-vinyl-
quinuclidinium} sulfate dehydrate. Acta Crystallogr 2010;E66:2443–2444.
Chirality DOI 10.1002/chir